Ovarian cancer severely affects women's health. Its morbidity ranks second among all the gynecologic malignant tumors while its morality ranks first. Ovarian cancer is a major cause for the death caused by gynecologic malignant tumors. Its onset is difficult to be noticed, while its progression is very fast. Among all the patients with ovarian cancer, 70-80% of them are diagnosed at a late stage. The 5-year survival rate of ovarian cancer patients is only about 30%. Neither the efficacy of traditional surgery nor that of chemical therapy is satisfactory. More than 70% of ovarian cancer will progress or relapse, even though the disease has been controlled temporarily. Further treatment will be even more difficult. Therefore, there is a need for a more effective therapy to increase the survival rate and improve the life quality of the patients with ovarian cancer.
Biological therapy is the fourth major tumor therapy while the other three are traditional surgery, radiation therapy and chemical therapy. As one type of biological therapies against tumors, tumor vaccine therapy has become a beneficial supplement to traditional therapies and has been used in the clinical treatment for many malignant tumors, because tumor vaccine can induce positive anti-tumor effect by the organism's immune system and it is both specific and targetable.
With continuous progress of biotechnology and more knowledge of the organisms' immune responses, tumor vaccine has been extensively developed. Tumor vaccine mainly comprises cell vaccine, antigen vaccine, anti-idiotype vaccine, peptide vaccine or epitope vaccine. Cell vaccine against a tumor is derived from auto- or allo-tumor cells or the rude extract thereof. Since it contains all the tumor antigens of an individual, it can induce an anti-tumor immune response to a certain extent. However, disadvantages such as oncogenicity and weak immunogenicity still exist. Antigen vaccine is a tumor specific or tumor associated antigen which is extracted from tumor cells. Its composition is more definite than cell vaccines, and the oncogenicity and auto immune response are reduced. Anti-idiotype vaccine is an internal image mimicking a key epitope of a tumor antigen, which is different from the original tumor antigen. Upon administration, it can destroy the immune tolerance which is inherent in organisms with tumors and trigger specific immune response by the organisms per se. Its preparation is easier than that of antigen vaccine and the side effect is slight. Peptide vaccine is a peptide with a pivotal anti-tumor effect. It is clear now that any tumor antigen shall firstly be degraded into short peptides by antigen presenting cells; then the key epitope peptides therein bind to major histocompatibility complex (MHC) molecules, thus triggering the anti-tumor effects of immune cells. It can be seen that the development of tumor vaccine is a progressive scientific exploration and epitope peptides bring out a new route for developing tumor vaccines in the future.
Epitope is a special chemical group within an antigen molecule which determines the antigenic specificity of an antigen, also known as antigenic determinant. Epitope is a basic unit for specific binding with T- or B-cell receptors and antibodies. In an immune response, the antigen epitopes recognized by T cells and B cells are different, which are called as T cell epitopes and B cell epitopes respectively. MHC molecule is a cell surface molecule which is highly polymorphic. They can present the epitope peptides to the immune cells, induce proliferation of the corresponding immune cell population, and exert specific anti-tumor effects. According to a classic theory, the molecules binding to MHC I molecules are mainly endogenous antigenic peptides, which are generally 8-12 amino acids in length. The MHC-peptide complex is transferred to the cell surface, where the complex is recognized by the receptor of CD8 T cells. The molecules binding to MHC II molecules mostly are exogenous antigenic peptides, which vary greatly in length, generally 9-25 amino acids in length. This MHC-peptide complex is transferred to the cell surface, where the complex is recognized by the receptor of CD4 T cells. CD4 T cell is also called as Th cell, which can be divided into two types, namely Th1 type and Th2 type, based on the cytokines secreted. Th1 mainly secrets IL-2, IFN-γ and TNF-β, while Th2 mainly secrets IL-4, IL-5, IL-6 and IL-13. CD8T cell is the classic CTL cell. Depending on the characteristics of immune responses by the organism against pathogens or tumors, specific Th and/or CTL epitopes may be selected to directionally induce Th and/or CTL response in the host. It is even possible to induce directional development of Th1 or Th2 immune response in the organism by selecting a Th1 epitope or Th2 epitope, thereby resulting in an effective induction and accurate regulation of immune response. Recent studies show that these two pathways are not completely independent from each other. The peptides obtained from treatment of exogenous antigens in the organism can also enter into MHC I molecule pathway and can be recognized by the receptor of CD8 T cells. It is a strong support in theory to the anti-tumor practice by using exogenous antigens. CD4T cells mostly exert non-specific anti-tumor effects only, and the tumor-killing effects are indirect; whereas specific CD8 T cells may kill tumor cells more effectively and more directly. If exogenous antigens can enter into MHC I molecule pathway, they might induce specific CD8T cells, thereby resulting in effective anti-tumor effects. In the meantime, it shows that the cell induction pathways for Th and CTL cells are closely associated. Functionally speaking, only when Th epitopes are present, can CTL epitopes induce immune responses or can induce immune responses more effectively. It is clear now that dendritic cells (DCs) and heat shock proteins are important for the above cross presentation. Therefore, identification of effective anti-tumor epitope peptides may provide a more accurate and effective means for mediating the anti-tumor immune response.
Currently, the methods for identifying epitope peptides mainly include enzymolysis; elution; synthesis of overlapping peptides; screening mimic epitopes by phage-display peptide library; predicting candidate epitope peptides by a computer, followed by experimental verification. Though the methodology for identifying epitope peptides is improving continuously, the operation thereof is still time-costing. In addition, the peptides obtained after screening might not be effective because of variation of tumors and the immune tolerance of the organisms against the tumors.
The epitope peptides of some malignant tumors such as colon carcinoma, melanoma, lymphoma, neuroglioma and prostate carcinoma have been prepared in some foreign countries, and some of them have entered into the clinical research stage and a preliminary efficacy has been established. There are few reports about the preparation and application of epitope peptides of ovarian cancer throughout the world.